Avelumab in combinations for lung cancer and update from ALEX study

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Published: 4 Jun 2018
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Dr Alice Shaw - Massachusetts General Hospital Cancer Center, Boston, USA

Dr Shaw speaks with ecancer at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting about results from the JAVELIN 101 trial of avelumab in combination with either criztonib or lorlatinib

She reports low efficacy and limiting toxicities in the crizotinib arm, whereas lorlatinib was better tolerated and more efficacious.

Dr Shaw also presents updates from the ALEX trial of alectinib, with longer follow up and a median PFS now available, and considers its role in future trials and combinations.

This presentation was in one of the first oral sessions at ASCO, the clinical science symposium for the metastatic non-small cell lung cancer track.

The focus of the whole session was on immunotherapy in patients with oncogene driven lung cancers.

So my presentation focussed on JAVELIN Lung 101 which was an early phase study of two different combinations.

One was the combination of avelumab, which is an anti-PD-L1 inhibitor, combined with crizotinib, a multi-targeted ALK/ROS/MET inhibitor.

The second combination was avelumab with the ALK and ROS selective TKI lorlatinib.

There’s a fair amount of preclinical data suggesting that there could be potential therapeutic promise by combining checkpoint inhibitors like avelumab with targeted therapies like crizotinib of lorlatinib.

This preclinical data really is the rationale for testing these two separate combinations.

I should say that the first combination of avelumab and crizotinib was tested in ALK negative lung cancer patients, so they did not have a target of crizotinib, and here we were really focussed on seeing whether or not there could be some immunomodulatory effects of crizotinib that could synergise with PD-L1 inhibitors like avelumab.

The second group, the avelumab combined with lorlatinib was specifically in patients with advanced ALK positive lung cancer.

So what I reviewed at the meeting was the safety and efficacy data for both of these combinations.

We found that the first combination of avelumab and crizotinib in ALK negative patients was not well tolerated.

There were actually five of twelve patients who experienced dose limiting toxicities and these were mostly increased transaminases suggesting hepatotoxicity.

We also did not see significant efficacy in this group of patients.

We had a response rate of about 16.7% with confirmed responses.

So, between the high rate of adverse events, including these dose limiting toxicities, as well as the relatively low efficacy that cohort was closed actually.

The second portion of this was the avelumab lorlatinib combination in ALK positive patients.

Here this was actually better tolerated.

We actually had no dose limiting toxicities and just the normal adverse events we would expect to see based on the safety profiles of each drug.

Here we did see fairly good efficacy. Most of these patients had been previously treated with two or more ALK inhibitors, so heavily pre-treated, and here the confirmed response rate was about 46% with the avelumab lorlatinib combination.

So overall safety was pretty well tolerated and efficacy was reasonable.

However, it should be noted that in a previous study we did of lorlatinib alone we also saw a response rate of about 46%, in fact.

So it’s not clear how much the avelumab has added to the avelumab lorlatinib combination or whether or not it was all the lorlatinib causing the good response rate that we saw.

So further follow up is needed; we’re still following these patients and we’ll be looking to establish the true durability of these responses just to get a sense of whether or not the combination does add more than just single agent lorlatinib.

That covers my next question then. Between those two I think that ties up the safety and efficacy quite nicely. We can move on to updates from the ALEX study.

Yes. Last year at ASCO, so ASCO 2007, we presented the primary analysis of the ALEX study. ALEX was a global randomised study comparing the second generation ALK inhibitor alectinib with the first generation inhibitor crizotinib in newly diagnosed patients with advanced ALK positive lung cancer.

Last year when we presented the data it was a very positive study – the PFS of alectinib was significantly longer than the PFS with crizotinib, as was time to CNS progression and pretty much all of the efficacy endpoints.

That actually led to FDA approval of alectinib for first line treatment of advanced ALK positive lung cancer.

At this year’s ASCO we actually presented an update, about ten extra months of follow-up, to the ALEX data.

Again, here we see that the progression free survival is significantly longer with alectinib than crizotinib.

The median, actually, with alectinib came out to close to 35 months and that’s as compared to 11 months with crizotinib.

So huge significant benefit in terms of PFS. We also saw a higher response rate with alectinib compared to crizotinib and pretty much all of the other efficacy endpoints were also strongly positive, including duration of response.

With longer follow-up we also saw continued good safety with the alectinib; compared to crizotinib it probably is a little bit better tolerated than crizotinib.

So overall I would say that the ALEX update is very important. It actually now gives us a median PFS for the alectinib group; it was not reached when I first presented the data and now with longer follow-up it’s coming in at 35 months which is really quite remarkable that a first line TKI can give us a PFS of approaching three years.

We saw that there were no new safety signals or worsening safety so this does confirm that alectinib is the standard first line treatment for our patients with advanced ALK positive lung cancer.

Between the ALEX update and the JAVELIN data, what does that mean for crizotinib?

Just even ALEX alone has pretty much led to replacement of crizotinib with alectinib.

Again, the PFS benefit that was seen initially when we first reported the ALEX study and now with this difference of 35 versus 11 months using a more potent and more brain penetrable ALK inhibitor first really does establish alectinib as the standard first line.

So we aren’t typically recommending crizotinib for our newly diagnosed ALK positive patients at this point.

And if the activity of avelumab is confirmed for the JAVELIN trial are there any indications that a combination of avelumab and alectinib might be worth investigating?

There was actually a presentation on Friday as well, after my presentation, of the combination of alectinib with atezolizumab, which is another PD-L1 inhibitor.

Dr Dong-Wan Kim presented this abstract and it was looking at a relatively small number of patients but treated with this combination.

Safety was actually quite good and the efficacy was very high in this TKI naïve group of patients.

A response rate exceeding 80%, durability as well.

However, it’s the same question again that how much of that was due just to the alectinib versus the combination of alectinib and atezolizumab.

When you compare two studies side by side, the alectinib-atezolizumab combination versus all the single arm data we have with alectinib alone, the data looks very similar.

So again it’s not clear that adding an immunotherapy to an ALK TKI is adding much efficacy.

We don’t know yet but there’s no clear signal of that.